(Z/E)-Endoxifen ([Z/E]-4-hydroxy-N-desmethyltamoxifen) are metabolites of (Z)-tamoxifen, with (Z) endoxifen likely being responsible for the majority of tamoxifen?s pharmacologic activity1,2,3,4. Endoxifen is formed in two steps by cytochrome P450 (CYP) 3A4 and CYP2D6, and then conjugated by phase II enzymes in the liver to inactive forms by sulfation or glucuronidation3,4,5. Some studies have shown that impaired metabolic formation of endoxifen is associated with worse clinical outcomes for tamoxifen-treated patients. As such, the National Cancer Institute (NCI), Division of Cancer Prevention (DCP) is proposing to evaluate administration of (Z/E)-endoxifen in a topical gel formulation as localized transdermal therapy (LTT) for breast cancer prevention. Use of this formulation would allow delivery of the active tamoxifen metabolite directly to the target tissue, thereby reducing systemic exposure and associated uterine and thromboembolic risks, as well as eliminating metabolic dependence. To support clinical studies with (Z/E)-endoxifen gel, NCI, DCP is seeking proposals from the Toxicology Contractors to conduct the following preclinical studies.